Methylphenidate was first prepared as a mixture of the erythro and threo racemates. Subsequent studies of the two racemic mixtures revealed that the therapeutic activity resides in the threo diastereomer.
Racemic threo methylphenidate hydrochloride is a mild nervous system stimulant which is marketed for the treatment of children with Attention Deficit Hyperactivity Disorder (ADHD). Further studies of the threo diastereomer revealed that the preferred therapeutic activity resides in the d-threo (or 2R,2'R enantiomer. More particularly, it has been found that the d-threo enantiomer is between five and thirty-eight times more active then the corresponding l-threo enantiomer. In addition, it has been shown that there are significant metabilic differences between the two enantiomers.
To date, there have been a few methods disclosed in the literature for preparing the d-threo enantiomer of methylphenidate hydrochloride. U.S. Pat. No. 2,957,880 discloses a rather tedious sequence involving the resolution of the amide derivative of the corresponding erythro isomer, conversion to the threo isomer, followed by the hydrolysis of the amide to the corresponding acid, and esterification of the resulting acid with methanol. In the Journal of Pharmacology and Experimental Therapeutics, Vol. 241, pgs. 152-158 (1987), the d-threo enantiomer is prepared by resolving the racemic mixture of threo methylphenidate employing (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate. In WO 97/27176, the d-threo enantiomer is prepared by resolving racemic threo methylphenidate employing a di-aroyltartaric acid, preferably a di-toluoyltartaric acid, whereas in WO 97/32851, the d-threo enantiomer is prepared by resolving racemic threo methylphenidate employing (-)-menthoxyacetic acid. Although the latter three processes are believed to be more efficient than the resolution method disclosed in U.S. Pat. No. 2,957,880, they all exhibit drawbacks which make them unattractive from a commercial standpoint. To wit, the use of (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate as the resolving agent in the commercial Pharmacology and Experimental Therapeutics article and the need for further recrystallizations to attain the desired purity renders the cost of the commercial process employing this method to be prohibitive. As to the latter two methods, they both involve the isolation of the free base form of the racemic mixture of threo methylphenidate prior to resolution. Accordingly, a need exists for a more practical and economic process for preparing the d-threo isomer of methylphenidate hydrochloride.